Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics

Histamine H3 receptor (H3R) antagonists have some antipsychotic properties although the clear molecular mechanism is still unknown. As actually the most effective and less side effective antipsychotics are drugs with multiple targets we have designed typical and atypical neuroleptics with an additional histamine H3 pharmacophore. The 4-(3-piperidinopropoxy)phenyl pharmacophore moiety has been linked to amitriptyline, maprotiline, chlorpromazine, chlorprothixene, fluphenazine, and clozapine. Amide, amine and ester elements have been used generally to maintain or slightly shift affinity at dopamine D2-like receptors (D2 and D3), to decrease affinity at histamine H1 receptors, and to obtain H3R ligands with low nanomolar or subnanomolar affinity. Change of effects at D1-like receptors (D1 and D5) were heterogeneous. With these newly profiled compounds different antipsychotic properties might be achieved.

Graphical abstractNew multiple target drugs based on marketed neuroleptics have been designed, prepared and profiled maintaining dopamine hD2/hD3 receptor affinities, reducing histamine hH1 receptor affinities and introducing high affinity at histamine hH3 receptors (H3R). hD1/hD5 binding was heterogeneously shifted. The addition of an H3R pharmacophore to different typical and atypical neuroleptics by amide, amine or ester linkages resulted in a new profile of potential antipsychotics with low nanomolar to subnanomolar H3R affinities.Figure optionsDownload full-size imageDownload as PowerPoint slide